Comparative analysis of KMT2A fusions in human models of acute myeloid leukemia

Pediatric acute myeloid leukemia (AML) frequently involves chromosomal rearrangements, particularly KMT2A (MLL) gene fusions, with the KMT2A-MLLT4 (KM4-AML) fusion being highly aggressive and associated with poor prognosis. This study presents a comparative analysis of transcriptomic and epigenetic profiles between human leukemia models harboring KM4-AML and KMT2A-MLLT3 (KM3-AML) fusions. Transcriptomic signatures of KM4-AML models closely resembled those of patient samples, underscoring the model's clinical relevance. Epigenetic analysis revealed distinct chromatin accessibility and methylation patterns between KM4-AML and KM3-AML, particularly in enhancer regions linked to aggressive leukemia phenotypes. PROM1 was identified as a potential biomarker for KM4-AML, with its overexpression correlating with poor prognosis. Furthermore, high-throughput drug screening identified dopamine receptor antagonists (DRAs) as promising therapeutic candidates showing selective response for KM4-AML models. Docking simulations and NMR assays confirmed favorable binding interactions between DRAs and S100A8, S100A9 and ANXA6. These findings provide insights into the molecular mechanisms driving KM4-AML and offer potential therapeutic avenues for treatment.